The ultimate goals of the proposed study are to: 1) characterize genetic involvement in skeletal maturation throughout childhood, 2) locate and determine the significance of as yet unknown genes influencing individual variation in skeletal maturation during childhood, and 3) evaluate the contributions of polymorphisms in candidate genes to individual variation in skeletal maturation during childhood. While the study of childhood growth patterns and sexual development has been the focus of much study, very little is presently known about processes involved in skeletal maturation. This is especially so regarding the genetics of childhood skeletal maturation. In this proposal, skeletal maturation, as distinguished from skeletal growth, refers to the process whereby sets of specific radiographically visible changes in skeletal features culminate in adult skeletal status in young adulthood. Skeletal maturity refers to status achieved by a given chronological age in childhood. Skeletal maturity is quantified as skeletal age, a value assigned to a bone or skeletal area that is the level of maturity expressed in years and months irrespective of the child's actual or chronological age. Skeletal age reflects different mechanisms at different stages of growth and development. During early childhood, it is largely a measure of the timing of ossification onset in bones. In mid-childhood, it is largely a measure of changes in bone shape, both individually and with respect to joint formation. Near the end of growth and development, during puberty, skeletal age is largely a measure of degree of epiphyseal fusion. Skeletal age is assessed in the proposed study from serial radiographs of the hand-wrist and the knee collected as part of the Fels Longitudinal Study. There are over 15,500 skeletal age assessments from hand-wrist radiographs taken from 1930 to the present, and some 7,750 assessments of skeletal age from knee radiographs taken between 1931 and 1987, of over 900 children participating at one time or another in the Fels Longitudinal Study who have been studied serially from infancy to at least 18 years. These individuals represent a total of 213 nuclear and extended families, most of which have family members from whom DNA has already been collected, or is presently being collected, as part of both previous and ongoing studies. These data offer an altogether unprecedented and thoroughly unique opportunity to elucidate the genetic architecture of skeletal maturation during childhood.